Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1C=C(C=C[CH:11]=1)C(OO)=O.C(S[C:15]1[N:19]([CH3:20])[N:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=1[C:25]1[N:37]([CH3:38])[C:28]2=[N:29][CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=[C:27]2[N:26]=1)C.[S:39]([O-:43])([O-])(=[O:41])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:39]([C:15]1[N:19]([CH3:20])[N:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[C:16]=1[C:25]1[N:37]([CH3:38])[C:28]2=[N:29][CH:30]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:32]=[C:27]2[N:26]=1)(=[O:43])=[O:41])[CH3:11]
Reactant: CCSc1c(-c2nc3cc(C(F)(F)F)cnc3n2C)c(C(F)(F)F)nn1C
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1c(-c2nc3cc(C(F)(F)F)cnc3n2C)c(C(F)(F)F)nn1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.35 g of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to a mixture of 0.24 g of 2-(5-ethylthio-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine and 5 ml of chloroform, under ice cooling, and the mixture was stirred at room temperature for 6 hours. A 10% aqueous sodium thiosulfate solution was poured into the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.24 g of 2-(5-ethylsulfonyl-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (Compound of Present Invention (26)).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18]>>[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:18]
Reactant: CNCCC#Cc1ccccn1
Reactant: O=C(Cl)c1cccc(F)c1
Product: CN(CCC#Cc1ccccn1)C(=O)c1cccc(F)c1
Yield: 38.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 3-fluorobenzoyl chloride (64 mg, 0.41 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 97/3 as eluent) to afford 34 mg of 3-fluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a brown oil (Yield: 39%).
Reaction SMILES: [CH3:1][N:2]1[CH:10]2[CH:5]([CH:6]=[C:7]([OH:11])[CH:8]=[CH:9]2)[CH:4]2[CH2:12][CH2:13][CH:14]([NH:15]CC3C=CC=CC=3)[CH:3]12>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:1][N:2]1[C:10]2[C:5]([CH2:6][C:7]([OH:11])=[CH:8][CH:9]=2)=[C:4]2[CH:12]=[CH:13][CH:14]=[C:3]12.[NH2:15][CH:14]1[CH:3]2[N:2]([CH3:1])[CH:10]3[CH:5]([CH:4]2[CH2:12][CH2:13]1)[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9]3
Reactant: CN1C2C=CC(O)=CC2C2CCC(NCc3ccccc3)C21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CN1C2C=CC(O)=CC2C2CCC(N)C21
Product: Cn1c2c(c3c1=CC=C(O)C3)C=CC=2
Yield: 115.7 %

Procedure:
20% Palladium hydroxide on carbon (1.4 g) was added to a solution of 1,2,3,3a,4,8a-hexahydro-4-methyl-3-phenylmethylaminocyclopent[b]indol-7-ol (14 grams) in ethanol (100 ml) and the mixture was hydrogenated at 45 psi H2 pressure using a Parr apparatus at 50° C. for 5 hours. The mixture was filtered and the solution was concentrated to give 3-amino-1,2,3,3a,4,8a-hexahydro-4-methylcyclopent[b]indol-7-ol 4-methylcyclopent[b]indol-7-ol (10.7 grams).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.C[Si]([C:13]#[N:14])(C)C.C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:3]([C:13]#[N:14])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ncccc1Br
Yield: 64.3 %

Procedure:
A mixture of 3-bromopyridine N-oxide (26.09 g; 150 mmol), trimethylsilyl cyanide (50 g; 504 mmol), and triethylamine (30.36 g, 300 mmol) in dry acetonitrile under nitrogen was refluxed for 20 hours. The mixture was concentrated in vacuo, the residue partitioned between methylene chloride (600 ml) 3 N sodium carbonate solution (250 ml), and the aqueous layer was extracted with 200 ml of methylene chloride. The combined organic layer was dried over sodium sulfate, concentrated in vacuo, and the residue was purified by flash chromatography (25% ethyl acetate in hexane) to afford 17.65 g (64.5%) of 3-bromo-2-cyano-pyridine as a solid, m.p. 93°-95° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](Br)[C:7]([O:11][CH3:12])=[CH:6][C:5]=1[O:13][CH3:14].[C:16]([O-])([O-])=O.[Cs+].[Cs+].CCO[C:25]([CH3:27])=O>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:25]([CH3:27])=[CH2:16])[C:7]([O:11][CH3:12])=[CH:6][C:5]=1[O:13][CH3:14]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1cc(Br)c(OC)cc1OC
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: O
Product: C=C(C)c1cc(C(=O)OC)c(OC)cc1OC

Procedure:
To potassium isopropylidene trifluoroborate (4.87 g, 32.7 mmol) and 5-bromo-2,4-dimethoxybenzoic acid methyl ester (7.5 g, 27.3 mmol) in TBF (195 ml) was added Cs2CO3 (26.6 g, 81.8 mmol) in water (39 ml). The reaction was degassed and Pd(PPh3)4 (1.58 g, 1.36 mmol) added. The reaction was heated at reflux for three days then quenched by adding water and extracted with EtOAc (×2). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to leave an orange solid. The product was taken up in EtOAc again and the precipitate filtered. The filtrate was evaporated to dryness to yield 5-isopropenyl-2,4-dimethoxy-benzoic acid methyl ester (6.2 g). 1H NMR (Me-d3-OD) 7.68 (1H, s), 6.66 (1H, s), 5.10-5.08 (1H, m), 5.02-5.00 (1H, m), 3.93 (3H, s), 3.92 (3H, s), 3.84 (3H, s), 2.08-2.06 (3H, m). MS: [M+H]+ 237.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([CH2:12]O)=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[Br:14][Si](C)(C)C>C(Cl)Cl>[Br:14][CH2:12][C:9]1[S:8][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:11][CH:10]=1
Reactant: C[Si](C)(C)Br
Reactant: OCc1ccc(-c2ccc(Cl)s2)s1
Solvent: ClCCl
Product: Clc1ccc(-c2ccc(CBr)s2)s1
Reaction time: 4 h
Yield: 58.9 %

Procedure:
To a solution of (5′-chloro-[2,2′]bithiophenyl-5-yl)-methanol (2.23 g, 9.66 mmol) in 65 mL of CH2Cl2 is added bromotrimethylsilane (3.82 mL, 29.0 mmol). After 4 h, the solution is concentrated in vacuo. The crude product is stirred in hot hexanes and filtered. The filtrate is concentrated and the title compound (1.67 g, 5.69 mmol) is obtained as a green solid. 1H NMR (CDCl3, 300 MHz) δ7.00 (d, 1H), 6.94 (m, 2H), 6.85 (d, 2H), 4.71 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH3:36][O:37][C:38]([C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)=[O:39]>>[CH3:36][O:37][C:38]([C:40]1[CH:45]=[C:44]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:27][C:28](=[O:33])[NH:29][S:30]5(=[O:32])=[O:31])=[CH:22][CH:21]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:4][CH:3]=2)[CH:43]=[CH:42][CH:41]=1)=[O:39]
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: COC(=O)c1cccc(B(O)O)c1
Product: COC(=O)c1cccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)c1

Procedure:
5-{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (119 mg, 0.2 mmol) was treated as described in general procedure G using 3-methoxycarbonylphenylboronic acid (108 mg, 0.6 mmol) to give 4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-3-carboxylic acid methyl ester.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:31])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]([C:28]#[N:29])=[N:15][C:14]=2[N:13]([CH3:30])[C:11]1=[O:12])(=[O:3])[CH3:2].[H][H]>[Pd].C(O)(=O)C>[C:1]([O:4][C@H:5]([CH3:31])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]([CH2:28][NH2:29])=[N:15][C:14]=2[N:13]([CH3:30])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(C#N)n2Cc2ccccc2)n(C)c1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(CN)n2Cc2ccccc2)n(C)c1=O

Procedure:
A suspension of (R)-1-(5-acetoxyhexyl)-7-benzyl-8-cyano-3-methylxanthine (850 mg, 2.0 mmol) and 10% palladium on carbon (300 mg) in glacial acetic acid (60 ml) was treated with hydrogen gas (80 psi) on a Parr shaker for 3 hours. After filtering through a pad of celite, the filtrate was concentrated under reduced pressure to provide the acetic acid salt of (R)-1-(5-acetoxyhexyl)-8-aminomethyl-7-benzyl-3-methylxanthine.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C@H:3]([N:28]1[CH2:32][CH2:31][C@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10]/[N:11]=[CH:12]/[C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([O:24][CH:25]([CH3:27])[CH3:26])[CH:17]=[C:18]([F:23])[CH:19]=3)[N:14]=2)=[CH:8][CH:9]=1.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O>C(Cl)Cl>[F:42][C:2]([F:1])([F:41])[C@H:3]([N:28]1[CH2:32][CH2:31][C@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[CH2:29]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:12]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[C:16]([O:24][CH:25]([CH3:27])[CH3:26])[CH:17]=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: CC(C)Oc1cc(F)cc2ccc(/C=N/Nc3ccc([C@@H](N4CC[C@H](NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)nc12
Agent: O=Ic1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)Oc1cc(F)cc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
To tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-((E)-2-((6-fluoro-8-isopropoxyquinolin-2-yl)methylene)hydrazinyl)pyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (157 mg, 0.266 mmol) in DCM (10 mL) was added iodosobenzene diacetate (94.2 mg, 0.292 mmol) and the reaction was stirred at ambient temperature for 2 hours. The reaction was concentrated to dryness and the residue purified by reverse phase chromatography (SP4, 12M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-8-isopropoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (124 mg, 79.3% yield) as a beige solid.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=O)[CH3:2].[C:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])#[N:10].C([O-])(=O)C.[NH4+].O>C(O)(=O)C.C1(C)C=CC=CC=1>[C:9](/[C:11](=[C:1](/[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)\[CH3:2])/[C:12]([O:14][CH3:15])=[O:13])#[N:10]
Reactant: CC(=O)c1cccs1
Reactant: COC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)/C(C#N)=C(/C)c1cccs1
Yield: 40.1 %

Procedure:
400 g of 2-acetylthiophene, 314 g of methyl cyanoacetate and 48.8 g of ammonium acetate were dissolved in a mixture of 153 ml of acetic acid and 1.5 l of toluene, and the resulting reaction solution was refluxed under heating for 8 hours while water was removed. The reaction solution was washed sufficiently with water and then dried over anhydrous magnesium sulfate. Removal of the solvent by distillation was followed by vacuum distillation (b.p. 110°-140° C./0.05 mmHg) to give 263.4 g of methyl 2-cyano-3-(2-thienyl)crotonate. (Yield 40%)
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][C@H:33]1[CH2:38][OH:39]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][C@H:33]5[CH2:38][OH:39])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:31])[F:30])[CH:3]=1
Reactant: OC[C@@H]1COCCN1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCOC[C@H]2CO)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3(R)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (3R)-Morpholin-3-yl-methanol following General Procedure C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:17]([CH:19]1[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].CCN(CC)CC.[CH3:39][N:40]=[C:41]=[O:42]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:16][CH2:15][N:14]([C:41](=[O:42])[NH:40][CH3:39])[CH2:13][CH2:12]1)[C:17]([CH:19]1[CH2:20][CH2:21][CH:22]([CH3:25])[CH2:23][CH2:24]1)=[O:18])=[O:4]
Reactant: CN=C=O
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)N1CCC(N(C(=O)C2CCC(C)CC2)c2cc(-c3ccccc3)sc2C(=O)OC)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.5 %

Procedure:
A solution of 3-[(4-methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (145 mg, 0.33 mmol) in CH2Cl2 (3.3 mL) was treated with Et3N (69 mL, 0.49 mmol) and methyl isocyanate (28.2 mg, 0.49 mmol). After stirring at room temperature for 18 h, starting material remained. Methyl isocyanate (28.2 mg, 0.49 mmol) was added to the reaction that was stirred for another 4 h. The solvent was evaporated and the residue was dissolved in EtOAc, washed with HCl (0.1 M) and brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using (5% MeOH/CH2Cl2) to provide 3-[(1-Methylcarbamoyl-piperidin-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (142 mg, 87% yield). 1H NMR (CDCl3, 400 MHz): 7.65 (m, 2H), 7.45 (m, 3H), 7.00 (s, 1H), 4.78 (m, 1H), 4.35 (q, 1H), 4.05 (dd, 1H), 3.90 (m, 1H), 3.85 (s, 3H), 2.85 (m, 2H), 2.75 (d, 3H), 1.95 (m, 2H), 1.80 (m, 1H), 1.70-1.55 (m, 5H), 1.50-1.25 (m, 3H), 1.10 (m, 1H), 0.78 (d, 3H), 0.75-0.58 (m, 2H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[N:18][CH:19]=1.CON(C)[C:24]([C:26]1[N:27]([CH2:31][CH3:32])[N:28]=[CH:29][CH:30]=1)=[O:25]>O1CCCC1>[Br:13][C:14]1[CH:15]=[C:16]([C:24]([C:26]2[N:27]([CH2:31][CH3:32])[N:28]=[CH:29][CH:30]=2)=[O:25])[C:17]([F:20])=[N:18][CH:19]=1
Reactant: CCn1nccc1C(=O)N(C)OC
Reactant: Fc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCn1nccc1C(=O)c1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diisopropylamine and tetrahydrofuran were combined and cooled to −20° C. n-Butyl lithium (2.5M in hexanes) was slowly added and the resulting mixture stirred at this temperature for 30 minutes. The temperature was lowered to −78° C. and neat 5-bromo-2-fluoropyridine was added (internal temperature was not allowed to exceed −68° C.). The reaction mixture was stirred at −78° C. for 40 minutes. The resulting mixture was added to a solution of 2-ethyl-2H-pyrazole-3-carboxylic acid methoxy-methyl-amide in tetrahydro-furan. The combined reaction mixture was stirred at −78° C. for 1 hour before the reaction mixture was slowly warmed to room temperature, and quenched with saturate aqueous ammonium chloride solution. The reaction mixture was extracted with dichloromethane, dried over sodium sulfate, and concentrated. The crude material was purified by flash chromatography on silica gel to afford (5-bromo-2-fluoro-pyridin-3-yl)-(2-ethyl-2H-pyrazol-3-yl)-methanone. MS: m/z 298.1+300.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](/[N:19]=[N:20]/[C:21]2[CH:26]=[CH:25][C:24]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29][OH:30])=[CH:23][CH:22]=2)[S:5][C:6]=1[CH:7]=[C:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].Cl[S:34]([OH:37])(=[O:36])=[O:35]>C1COCC1>[S:34]([OH:37])([O:30][CH2:29][CH2:28][N:27]([C:24]1[CH:23]=[CH:22][C:21](/[N:20]=[N:19]/[C:4]2[S:5][C:6]([CH:7]=[C:8]3[C:9](=[O:18])[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:16]3=[O:17])=[C:2]([Cl:1])[N:3]=2)=[CH:26][CH:25]=1)[CH2:31][CH3:32])(=[O:36])=[O:35]
Reactant: O=S(=O)(O)Cl
Reactant: CCN(CCO)c1ccc(/N=N/c2nc(Cl)c(C=C3C(=O)c4ccccc4C3=O)s2)cc1
Solvent: C1CCOC1
Product: CCN(CCOS(=O)(=O)O)c1ccc(/N=N/c2nc(Cl)c(C=C3C(=O)c4ccccc4C3=O)s2)cc1
Temperature: 0 °C

Procedure:
0.5 g (1.07 mmol) 2-{[4-chloro-2-((E)-{4-[ethyl(2-hydroxyethyl)amino]-phenyl}-diazenyl)-1,3-thiazol-5-yl]methylidene}-1H-indene-1,3(2H)-dione were dissolved in 50 ml THF and cooled to 0° C. Then 0.19 g (1.60 mmol) chlorosulfonic acid were added slowly drop by drop with stirring. After the addition was completed, the reaction mixture was heated under reflux for 4 hours, allowed to cool to room temperature and stirred overnight. After further cooling in an ice bath the formed precipitate was filtered off, washed with a little cold THF and dried at 40° C. in vacuum.
Reaction SMILES: [OH-].[Na+:2].[CH:3]1[CH:8]=[N:7][CH:6]=[C:5]([CH2:9][C:10]([P:16]([OH:19])([OH:18])=[O:17])([P:12]([OH:15])([OH:14])=[O:13])[OH:11])[CH:4]=1.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>O.C(O)C>[CH:3]1[CH:8]=[N:7][CH:6]=[C:5]([CH2:9][C:10]([P:12]([O-:14])([OH:15])=[O:13])([P:16]([OH:19])([OH:18])=[O:17])[OH:11])[CH:4]=1.[Na+:2]
Reactant: O=P(O)(O)C(O)(Cc1cccnc1)P(=O)(O)O
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=P([O-])(O)C(O)(Cc1cccnc1)P(=O)(O)O
Temperature: 50 °C
Yield: 90 %

Procedure:
A solution of sodium hydroxide (7.4 g, 1 eq.) in a mixture of water/ethanol (50%, v/v) (150 ml) was added drop-wise to a suspension of risedronic acid (50 g) and 5 g of EDTA (ca. 10% on a dry per-weight basis) in a mixture of water/ethanol (50%, v/v) (850 ml) at reflux temperature. The reaction mixture was stirred at reflux temperature until the pH was stable at about 4.2-4.7. The reaction mixture was cooled to a temperature of about 50° C. The precipitate was then filtered, washed twice with 50 ml mixture of water/ethanol (50%, v/v) and then with ethanol (1×50 ml) and dried over night at 50° C. to give 48.5 g (85%) of sodium risedronate white crystal substance of form B (water content by thermogravimetric analysis was 5.5%-7.5%). Less than 50 ppm of iron was found in the product by AES.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[N:24]=[N:25][NH:26][N:27]=4)[CH:18]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:28]=1.[C:29](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[CH3:29][N:25]1[N:26]=[N:27][C:23]([C:19]2[CH:18]=[C:17]([N:14]3[CH2:13][C@H:12]4[N:8]([CH2:9][CH2:10][CH2:11]4)[C:7]4[N:28]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[C:15]3=[O:16])[CH:22]=[CH:21][CH:20]=2)=[N:24]1.[CH3:29][N:27]1[C:23]([C:19]2[CH:18]=[C:17]([N:14]3[CH2:13][C@H:12]4[N:8]([CH2:9][CH2:10][CH2:11]4)[C:7]4[N:28]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[C:15]3=[O:16])[CH:22]=[CH:21][CH:20]=2)=[N:24][N:25]=[N:26]1
Reactant: O=C([O-])[O-]
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn[nH]n3)c1)C2=O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nnn(C)n3)c1)C2=O
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nnnn3C)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %
Yield: 15 %

Procedure:
(S)-9-Methylthio-5-[3-(2H-tetrazol-5-yl)phenyl]-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (283 mg, 0.717 mmol) obtained in Step 1 was dissolved in DMF (7 mL), and the mixture was stirred at room temperature for 2 hours after adding potassium carbonate (149 mg, 1.08 mmol) and methyl iodide (0.0670 mL, 1.08 mmol). Thereafter, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The residue obtained upon concentration under reduced pressure was then purified by silica gel column chromatography to give (S)-5-[3-(2-methyl-2H-tetrazol-5-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (221 mg, 75%) and (S)-5-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (44.9 mg, 15%).
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[C:6]1([CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]([NH2:21])[CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[O:46][CH3:47])[CH2:27][CH:28]1[C:34]2[CH:35]=[C:36]([O:41][CH3:42])[C:37]([O:39][CH3:40])=[CH:38][C:33]=2[CH2:32][CH2:31][CH2:30][NH:29]1>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[O:46][CH3:47])[CH2:27][CH:28]1[C:34]2[CH:35]=[C:36]([O:41][CH3:42])[C:37]([O:39][CH3:40])=[CH:38][C:33]=2[CH2:32][CH2:31][CH2:30][N:29]1[CH2:2][C:3]([NH:21][CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:13]1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: NC1CC(c2ccccc2)c2ccccc21
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2CC(=O)NC2CC(c3ccccc3)c3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-bromoacetyl bromide with rac-3-phenyl-indan-1-ylamine and 1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine.
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:4].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br.O>CS(C)=O>[CH:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[C:21]([O:20][CH3:19])[CH:22]=2)[C:6]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:4]
Reactant: COc1cccc(CBr)c1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1c(C=O)c2ccccc2n1Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.40 g, 60.0 mmol) was cooled to 0° C., and anhydrous methyl sulfoxide (75.0 mL, 1.06 mol) was added. The mixture was stirred at 0° C. for 15 minutes before a solution of ethyl 3-formyl-1H-indole-2-carboxylate (10.9 g, 50.2 mmol, Lit. J. Heterocyclic Chem. 1997, 34, 1431.) in 75 mL of methyl sulfoxide was added over a 20 minute period. The resulting solution was warmed to room temperature and stirred for 1 hour. 3-Methoxybenzylbromide (9.8 mL, 70.0 mmol) was added, and the solution was heated at 60° C. for 16 hours. The solution was cooled and poured into water (500 mL). The aqueous solution was extracted with ethyl acetate (3×), and the combined organic extracts were washed with 1 N hydrochloric acid (2×), water, and brine. The solution was dried over anhydrous magnesium sulfate and concentrated in vacuo. Trituration of the residue with 33% hexane/Et2O provided the title compound as a solid (13.8 g, 81%). The product had: 1H NMR (300 MHz, acetone-d6) δ 10.61 (s, 1 H), 8.43 (d, 1 H), 7.61 (d, 1 H), 7.30-7.45 (m, 2 H), 7.19 (dd, 1 H), 6.80 (dd, 1 H), 6.63-6.74 (m, 2 H), 5.88 (s, 2 H), 4.48 (dq, 2 H), 3.70 (s, 3 H), 1.37 (t, 3 H); mass spectroscopy gave MH+=338.1 (calc'd exact mass for C20H19NO4=337.13).